The Philadelphia chromosome-positive (Ph+) leukemias, including chronic myeloid leukemia (CML) and Ph+ B- cell acute lymphoblastic leukemia (B-ALL), are prevalent blood cancers for which our current therapies are inadequate. While BCR-ABL tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have replaced hematopoietic stem cell transplantation (HSCT) as initial therapy for CML, complete molecular remissions are rare and acquired resistance to TKI therapy is a significant clinical problem. Eligible Ph+ B-ALL patients undergo allogeneic HSCT in first remission following chemotherapy, but over half will relapse. Hence, it is likely that current therapy will not cure most Ph+ leukemia patients, and effective methods to eradicate residual leukemia are needed. This is a collaborative, dual-PI application from two senior clinician-scientists focused on the preclinical development of novel transfusion-based cellular therapies designed to eliminate residual disease in Ph+ leukemia patients, leading to permanent cure. To accomplish these goals, we will utilize a well- characterized mouse model of CML and Ph+ B-ALL to determine the efficacy and cellular mechanisms of adoptive immunotherapy with allogeneic T-lymphocytes or natural killer (NK) cells. To extend the benefits of NK cell immunotherapy to lymphoid malignancies, we will continue the preclinical development of NK cells engineered to express activating receptors that recognize ligands on B-lymphoid leukemia cells (CD19 and CD20), and test their efficacy in an in vivo immunotherapy model against human Ph+ B-ALL in NOD/SCID/[unreadable]c mice. Finally, having demonstrated that HSC in CML are uniquely dependent on selectins and their ligands for homing and engraftment in mice, we will develop clinically relevant methods for blocking engraftment of leukemic stem cells without affecting normal HSC. Throughout the application, a major emphasis will be placed on translation of novel findings to the clinic. Together, these studies should yield important new knowledge that will improve the effectiveness of adoptive immunotherapy and autologous HSCT for Ph+ leukemia, and increase the proportion of patients that are cured of their disease. PHS 398/2590 (Rev. 11/07) Page 2 Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): Van Etten R.A./Klingemann H.K.